Digital spatial proteomic profiling reveals immune checkpoints as biomarkers in lymphoid aggregates and tumor microenvironment of desmoplastic melanoma

Authors

David G. Su, Department of Surgery, Yale School of Medicine, New Haven, Connecticut, USA.
David A. Schoenfeld, Department of Medical Oncology, Yale School of Medicine, New Haven, Connecticut, USA.
Wael Ibrahim, Department of Pathology, University of Miami Miller School of Medicine, Miami, Florida, USA.
Raysa Cabrejo, Department of Plastics and Reconstructive Surgery, Dartmouth Hitchcock Medical Center, Lebanon, New Hampshire, USA.
Dijana Djureinovic, Department of Medical Oncology, Yale School of Medicine, New Haven, Connecticut, USA.
Raymond Baumann, Department of Pharmacology, Yale School of Medicine, New Haven, Connecticut, USA.Follow
David L. Rimm, Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, USA.Follow
Sajid A. Khan, Department of Surgical Oncology, Yale School of Medicine, New Haven, Connecticut, USA.Follow
Ruth Halaban, Department of Dermatology, Yale School of Medicine, New Haven, Connecticut, USA.
Harriet M. Kluger, Department of Medical Oncology, Yale School of Medicine, New Haven, Connecticut, USA.Follow
Kelly Olino, Department of Surgical Oncology, Yale School of Medicine, New Haven, Connecticut, USA.Follow
Anjela Galan, Department of Dermatology, Yale School of Medicine, New Haven, Connecticut, USA.
James Clune, Department of Surgery, Yale School of Medicine, New Haven, Connecticut, USA james.clune@yale.edu.Follow

Document Type

Article

Publication Title

Journal for immunotherapy of cancer

Abstract

BACKGROUND: Desmoplastic melanoma (DM) is a rare melanoma subtype characterized by dense fibrous stroma, a propensity for local recurrence, and a high response rate to programmed cell death protein 1 (PD-1) blockade. Occult sentinel lymph node positivity is significantly lower in both pure and mixed DM than in conventional melanoma, underscoring the need for better prognostic biomarkers to inform therapeutic strategies. METHODS: We assembled a tissue microarray comprising various cores of tumor, stroma, and lymphoid aggregates from 45 patients with histologically confirmed DM diagnosed between 1989 and 2018. Using a panel of 62 validated immune-oncology markers, we performed digital spatial profiling using the NanoString GeoMx platform and quantified expression in three tissue compartments defined by fluorescence colocalization (tumor (S100+/PMEL+/SYTO+), leukocytes (CD45+/SYTO+), and non-immune stroma (S100-/PMEL-/CD45-/SYTO+)). RESULTS: We observed higher expression of immune checkpoints (lymphocyte-activation gene 3 [LAG-3] and cytotoxic T-lymphocyte associated protein-4 [CTLA-4]) and cancer-associated fibroblast (CAF) markers (smooth muscle actin (SMA)) in the tumor compartments of pure DMs than mixed DMs. When comparing lymphoid aggregates (LA) to non-LA tumor cores, LAs were more enriched with CD20+B cells, but non-LA intratumoral leukocytes were more enriched with macrophage/monocytic markers (CD163, CD68, CD14) and had higher LAG-3 and CTLA-4 expression levels. Higher intratumoral PD-1 and LA-based LAG-3 expression appear to be associated with worse survival. CONCLUSIONS: Our proteomic analysis reveals an intra-tumoral population of SMA+CAFs enriched in pure DM. Additionally, increased expressions of immune checkpoints (LAG-3 and PD-1) in LA and within tumor were associated with poorer prognosis. These findings might have therapeutic implications and help guide treatment selection in addition to informing potential prognostic significance.

DOI

10.1136/jitc-2023-008646

Publication Date

3-21-2024

Recommended Citation

Su, David G.; Schoenfeld, David A.; Ibrahim, Wael; Cabrejo, Raysa; Djureinovic, Dijana; Baumann, Raymond; Rimm, David L.; Khan, Sajid A.; Halaban, Ruth; Kluger, Harriet M.; Olino, Kelly; Galan, Anjela; and Clune, James, "Digital spatial proteomic profiling reveals immune checkpoints as biomarkers in lymphoid aggregates and tumor microenvironment of desmoplastic melanoma" (2024). Surgery. 194.
https://scholar.bridgeporthospital.org/surgery/194

Identifier

38519058 (pubmed); PMC10961546 (pmc); 10.1136/jitc-2023-008646 (doi); jitc-2023-008646 (pii)